Rejection or Infection? A Case of Kidney Allograft Non-Human Leukocyte Antigen Antibody-Mediated Rejection and Cytomegalovirus Viremia

Introduction: Antibody-mediated rejection (AMR) is a leading cause of kidney allograft failure, typically linked to human leukocyte antigen (HLA) donor-specific antibodies (DSA). However, a growing body of evidence highlights the significance of non-HLA AMR, involving antibodies against endothelial antigens such as angiotensin II type 1 receptor (AT1R), MICA/B, and endothelin A receptor (ETAR). These antibodies may arise following endothelial injury from inflammation, ischemia, or infection. This case presents a rare instance of non-HLA AMR possibly triggered by cytomegalovirus (CMV) infection. Case Description: A 62-year-old woman with end-stage renal disease due to diabetic nephropathy received a deceased donor kidney transplant with thymoglobulin induction. Maintenance immunosuppression included tacrolimus, mycophenolate mofetil (MMF), and prednisone. Four months post-transplant, she presented with elevated creatinine (2.03 mg/dL from baseline 0.9–1.1), 1g proteinuria, fatigue, headache, poor appetite, diarrhea, and edema. She was found to have CMV viremia (PCR 184,000 IU/mL) and an elevated dd-cfDNA (6.7[CY1] %), suggesting AMR. Allograft biopsy showed C4d positivity, consistent with AMR, but her HLA-DSA panel was negative. Due to active CMV infection, AMR treatment was deferred. MMF was held, and she was started on valganciclovir. Non-HLA antibody testing revealed a positive anti-endothelial cell antibody (AECA) crossmatch. Anti-MICA and anti-AT1R antibodies were negative. After antiviral treatment, CMV PCR fell to <200 IU/mL, creatinine normalized to baseline, dd-cfDNA declined to 2.7%, and repeat AECA crossmatch was negative. Discussion: This case highlights a possible link between CMV infection and the development of non-HLA AMR via AECA production. While rare, CMV-induced endothelial injury may play a role in triggering non-HLA alloimmune responses. Management centered on treating the infection rather than initiating AMR therapy led to recovery of graft function and resolution of immune markers. This underscores the need for further research into non-HLA AMR mechanisms and optimal management strategies.